To dock CombiUgi UClib005 (1512 compounds) against falcipain-2 using the covalent docking option of GOLD. This library has chloroacetic acid as a common component to serve as the electrophile in the irreversible docking.
Procedure
The target of interest is the falcipain-2 enzyme. A crystal structure was published in Jan 2009 (3BPF, Kerr et al) with the covalently-bound inhibitor E64.
The crystallographic unit contains 4 monomers, of which the B monomer is identified (in the paper) as of highest quality ("our structural analyses involve monomer B from FP2 and monomer A from FP3, the best resolved monomer from each complex"). The B monomer was extracted, waters removed and hydrogens added (with GOLD's GUI). The histidine close to the cysteine SH was deprotonated at the pro ("near") N (in common with how other proteases were prepared by Astex in their Diverse Set).
The dataset of Ugi products was supplied as SMILES strings. The Cl was moved to atom position 1 (for convenience when setting up the covalent docking). CORINA was used to create all stereoisomers and add hydrogens ("./corina -i t=smiles -d stergen -d wh ClAtStart.txt inhibitors.sdf"). Finally, the Cl was replaced by S (required for covalent docking).
The dataset was covalently docked using each of Goldscore, ASP and Chemscore using GOLD's auto settings. Only the top scoring pose for each stereoisomer was retained.
Results
In assessing the results, only the top scoring stereoisomer for a particular molecule is used
Ranked Suicide Inhibitor Library-1 according to Goldscore Results spreadsheet
Discussion
Of the three scoring functions, only Goldscore was able to reproduce the crystallographic pose of E64 and score it highly, albeit not as highly as we would wish. (Note to self: It might be worth including other known actives to see the performance - especially known actives which are closer in structure to the Ugi products.)
The results are given for Goldscore. The top-ranked hit looks like a big ball of grease and so it might not be a reliable lead. The other top-ranked hits seem reasonable though.
Objective
To dock CombiUgi UClib005 (1512 compounds) against falcipain-2 using the covalent docking option of GOLD. This library has chloroacetic acid as a common component to serve as the electrophile in the irreversible docking.Procedure
The target of interest is the falcipain-2 enzyme. A crystal structure was published in Jan 2009 (3BPF, Kerr et al) with the covalently-bound inhibitor E64.The crystallographic unit contains 4 monomers, of which the B monomer is identified (in the paper) as of highest quality ("our structural analyses involve monomer B from FP2 and monomer A from FP3, the best resolved monomer from each complex"). The B monomer was extracted, waters removed and hydrogens added (with GOLD's GUI). The histidine close to the cysteine SH was deprotonated at the pro ("near") N (in common with how other proteases were prepared by Astex in their Diverse Set).
The dataset of Ugi products was supplied as SMILES strings. The Cl was moved to atom position 1 (for convenience when setting up the covalent docking). CORINA was used to create all stereoisomers and add hydrogens ("./corina -i t=smiles -d stergen -d wh ClAtStart.txt inhibitors.sdf"). Finally, the Cl was replaced by S (required for covalent docking).
The dataset was covalently docked using each of Goldscore, ASP and Chemscore using GOLD's auto settings. Only the top scoring pose for each stereoisomer was retained.
Results
In assessing the results, only the top scoring stereoisomer for a particular molecule is used
Ranked Suicide Inhibitor Library-1 according to Goldscore Results spreadsheet
Discussion
Of the three scoring functions, only Goldscore was able to reproduce the crystallographic pose of E64 and score it highly, albeit not as highly as we would wish. (Note to self: It might be worth including other known actives to see the performance - especially known actives which are closer in structure to the Ugi products.)
The results are given for Goldscore. The top-ranked hit looks like a big ball of grease and so it might not be a reliable lead. The other top-ranked hits seem reasonable though.
Conclusion